Prophylactic and therapeutic composition for circulatory disorders and method of treatment

ABSTRACT

A prophylactic and therapeutic agent for circulatory disorders, comprising a pyrazolone derivative of the formula: ##STR1## wherein R 1  represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms or an alkoxycarbonylalkyl group having a total carbon number of 3 to 6; R 2  represents a hydrogen atom, an aryloxy group, an arylmercapto group, an alkyl group having 1 to 5 carbon atoms or hydroxyalkyl group having 1 to 3 carbon atoms or R 1  and R 2  taken together represent an alkylene group having 3 to 5 carbon atoms; R 3  represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzyl group, a naphthyl group, or a phenyl group which is unsubstituted or substituted with 1 to 3 substituents which are the same or different selected from the group consisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms, hydroxyalkyl groups having 1 to 3 carbon atoms, alkoxycarbonyl groups having total carbon number of 2 to 5, alkylmercapto groups having 1 to 3 carbon atoms, alkylamino groups having 1 to 4 carbon atoms, dialkylamino groups having total carbon number of 2 to 8, halogen atoms, trifluoromethyl group, carboxyl group, cyano group, hydroxyl group, nitro group, amino group and acetamide group, or a pharmaceutically acceptable salt thereof as an active ingredient. The agent of the present invention is useful as a prophylactic and therapeutic agent for circulatory disorders, particularly as an inhibitor against lipid peroxidation and/or an agent for normalizing cerebral dysfunctions.

. .This application.!. .Iadd.This is a continuation of application Ser.No. 07/745,069, filed on Aug. 14, 1991, now abandoned, which .Iaddend.isa continuation-in-part, of application Ser. No. 862,091, filed May 12,1986. now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a prophylactic and therapeutic agent forcirculatory disorders, more particularly to a prophylactic andtherapeutic agent for cerebral, cardiac or peripheral circulatorydisorders accompanied with various ischeric diseases, especially to aprophylactic and therapeutic agent for circulatory disorders which isuseful as an inhibitor against lipid peroxidation and/or an agent fornormalizing cerebral dysfunctions.

In the specification, the term "circulatory disorders" means diseasesdue to circulatory disorder.

In cerebral, cardiac or peripheral circulatory disorders, as a result ofischemia (the state where little blood is supplied to tissues), activeoxygens (OH.radical, superoxide, etc.) formed in the tissues therearoundact on unsaturated fatty acids including arachidonic acid liberated fromcell membranes, to form peroxidized lipids. Such changes will occur notonly during ischemia, but also further will be accelerated and advancedby reoxidation through the blood refeeding after the ischemia to causedamage of cell membrane enriched in unsaturated fatty acids, destructionof surrounding tissues, destruction of blood vessel endothelium, bloodvessel spasms or cerebral edema, etc., and the condition of disease willbe advanced according to a vicious circle of a series of thesereactions, as is well known in the art ("Cerebral Ischemia and CellDisorder", edited by Takao Asano, Neuron Co., 1980; "Cerebral Ischemiaand Free Radical", edited by Takao Asano, Neuron Co., 1983).

Accordingly, if lipid peroxidation by active oxygen could be inhibited,it would be possible to prevent destruction of cell membrane,destruction of blood vessel endothelium, blood vessel spasm, cerebraledema, etc., and give a prophylactic or therapeutic agent forcirculatory disorders of a new type which can act on the cause of adisease, as different from the medicines of the prior art whichameliorates circulation by increasing the blood flow. Particularly, inrecent years, effectiveness of such vasodilators is considerted to bedoubtful and it is even said to be rather an adverse effect in cerebralinsufficiency in the acute stage, and therefore such a pharmaceutical isfurther becoming more important.

As described above, peroxidized lipids is considered to be formed by theaction of active oxygen as a result of ischemia. As the medicines whichcan inhibit lipid peroxidation by active oxygen, there have been knownvitamin E, idebenone represented by the following formula: ##STR2##(Biochemical and Biophysical Research Communications 125, 1046 (1984);Report from Takeda Kenkyusho 44, 30 (1985)) and nizofenone representedby the following formula: ##STR3## (Journal of Neurochemistry, 37, 934(1981)).

However, these medicines have drawbacks such that vitamin E has onlyunsatisfactory action, that idebenone and nizofenone are prepared bylengthy synthetic routes, that idebenone is considered to involve aproblem in formation of a preparation for injection due to difficulty insolubilizing in water and also that nizofenone has potent centralnervous system depressant activity Study of Pharmaceuticals (IyakuhinKenkyu) 16, 1 (1985)!.

Particularly, as the cerebral circulatory disorders, there may bementioned various cerebral diseases such as cerebrovascular disorders,cerebral dysfunctions, vascular dementia, cerebrovascular tissue lesionsaccompanied with aging, etc. In these diseases symptoms such asconsciousness disorders, lowering in memory, etc., based on cerebraldysfunctions, namely the abnormal pattern of electroencephalogram willbe caused. Therefore, as the medicine to be used for prophylaxis andtherapy of these cerebral disorders, those having antagonistic actionagainst drowsy pattern of electroencephalogram during cerebral functionabnormality (abnormal electroencephalogram) (hereinafter referred to as"electroencephalogram normalizing action") have been desired.

As a medicine having such pharmacological activity, thyrotropinereleasing hormone (TRH) having a chemical structure ofL-pyrroglutamyl-L-histidyl-L-prolineamide has been knownNeuropharmacology, 14, 489 (1975); Journal of Pharmacology andExperimental Therapeutics 193, 11 (1975)!. However, TRH exhibites anaction which is deemed to be a side action in clinic, also againstelectroencephalogram under normal state. Also, since TRH is atripeptide, there is a fear that it has a problem in stability in livingbody or absorption by oral administration, and the dosage form at thepresent time is only by way of intravenous administration.

Various pyrazolone derivatives have been known in the art.

Japanese Unexamined Patent Publication No. 13766/1976 discloses apyrazolin-5-one derivative represented by the following formula and itsuse as antithrombus agent: ##STR4## Japanese Unexamined PatentPublication No. 141517/1984 discloses use of the same compound as atherapeutic agent for cardiac infarction, inflammation, astham, etc.,after myocardial ischemia,

Japanese Unexamined Patent Publication No. 175469/1984 discloses apyrazolin-5-one derivative of the following formula and its use as alipoxygenase inhibitor: ##STR5## (wherein X represents a group --CH₂ CH₂O--, --CH₂ CH₂ S--, etc., and R represents an aryl group).

Japanese Patent Publication No. 512/1984 discloses a pyrazolin-5-onederivative and its use as a diuretic, antihypertensive, andantithrombosis: ##STR6## (wherein R₁ represents a hydrogen atom or anamino group, R₂ an aryl group and X represents a group --CH₂ CH₂ --,etc.).

However, these derivatives are not of the type in which all the arylgroups are bonded directly to the 1-position of the pyrazolin-5-onenucleus, and there is no description about the effect on cerebraldysfunctions including electroencephalogram normalizing action at all.

Also, West Germany Patent No. 28 36 891 discloses a pyrazolin-5-onederivative of the following formula and its use as antiinflammatoryagent: ##STR7## (wherein R₁ and R₂ represent a hydrogen atom or asubstituent).

However, there is no description about the action of inhibiting lipidperoxidation by active oxygen. Also, while the compound represented bythe formula (B) is stated to be effective in models of ischemic heartdiseases using rats, rabbits and dogs, it is ineffective in a modelusing pigs, of which circulation state is approximate to that of humanheart. This result well coincides with the report that it is ineffectivefor ischemic heart diseases in human being (European Journal ofPharmacology, 114, 189 (1985)). Also, there is no description about aspecific action concerning protection after recirculation of cerebralischemia.

SUMMARY OF THE INVENTION

Accordingly, the present inventors have studied intensively in order toprovide a prophylactic and therapeutic agent for circulatory disordersin humans and mammals, more particularly a prophylactic and therapeuticagent for cerebral, cardiac or peripheral circulatory disordersaccompanied with various ischemic diseases, especially a prophylacticand therapeutic agent for circulatory disorders which is useful as aninhibitor against lipid peroxidation and/or an agent for normalizingcerebral dysfunctions. Consequently, they have found that a pyrazolonederivative represented by the following Formula (I) has a potentinhibitory action against lipid peroxidation, and has an antagonisticaction against . .browsy.!. .Iadd.drowsy .Iaddend.pattern ofelectroencephalogram in an animal model under the state approximate tothe practical condition of disease and protective action such asrestration of electroencephalogram after recirculation of cerebralischemia, and thus it is useful as a prophylactic and therapeutic agentfor circulatory disorders: ##STR8## wherein R₁ represents a hydrogenatom, an aryl group, an alkyl group having 1 to 5 carbon atoms or analkoxycarbonylalkyl group having a total carbon number of 3 to 6; R₂represents a hydrogen atom, an aryloxy group, an arylmercapto group, analkyl group having 1 to 5 carbon atoms or hydroxyalkyl group having 1 to3 carbon atoms; or R₁ and R₂ taken together represent an alkylene grouphaving 3 to 5 carbon atoms; R₃ represents a hydrogen atom, an alkylgroup having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, a benzylgroup, a naphthyl group, or a phenyl group which is unsubstituted orsubstituted with 1 to 3 substituents which are the same or differentselected from the group consisting of alkyl groups having 1 to 5 carbonatoms, alkoxy groups having 1 to 5 carbon atoms, hydroxyalkyl groupshaving 1 to 3 carbon atoms, alkoxycarbonyl groups having total carbonnumber of 2 to 5, alkylmercapto groups having 1 to 3 carbon atoms,alkylamino groups having 1 to 4 carbon atoms, dialkylamino groiupshaving total carbon number of 2 to 8, halogen atoms, trifluoromethylgroup, carboxyl group, cyano group, hydroxyl group, nitro group, aminogroup and acetamide group,

The present invention has been accomplished on the basis of such afinding.

The prophylactic and therapeutic agent for circulatory disorders of thepresent invention comprises a pyrazolone derivative represented by theabove Formula (I) or its pharmaceutically acceptable salts as the activeingredient.

The compound (I) to be used in the present invention can also take thestructures shown by the following Formula (I') or (I"): ##STR9##accordingly, the compounds having the structure of the above formula(I') or (I") are also included within the active ingredient of thepresent invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the above formula (I), the aryl group represented by R₁ may include aphenyl group and phenyl groups which are substituted with substituentssuch as methyl, butyl, methoxy, butoxy, hydroxy groups and a chlorineatom, etc. The alkyl group having 1 to 5 carbon atoms represented by R₁,R₂ and R₃ may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertbutyl, pentyl groups and the like. Thealkoxycarbonylalkyl group having total carbon number of 3 to 6represented by R₁ may include methoxycarbonylmethyl,ethoxycarbonylmethyl, propoxycarbonylmethyl, methoxycarbonylethyl,methoxycarbonylpropyl groups and the like. The aryloxy groupsrepresented by R₂ may include phenoxy, p-methylphenoxy, p-methoxphenoxy,p-chlorophenoxy, p-hydroxyphenoxy groups and the like. The arylmercaptogroup represented by R² may include phenylmercapto,p-methylphenylmercapto, p-methoxypenylmercapto, p-chlorophenylmercapto,p-hydroxyphenylmercapto groups and the like. The hydroxyalkyl grouphaving 1 to 3 carbon atoms represented by R₂ or R₃ may includehydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl groups and the like. Thecycloalkyl group having 5 to 7 carbon atoms represented by R₃ mayinclude cyclopentyl, cyclohexyl, cycloheptyl groups and the like. As thesubstituent for the phenyl group in the definition of R₃, the alkoxygroup having 1 to 5 carbon atoms may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, pentyloxy groups and the like the alkoxycarbonylgroup having total carbon number of 2 to 5 may include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl groups and the like; thealkylmercapto group having 1 to 3 carbon atoms may includemethylmercapto, ethylmercapto, propylmercapto groups and the like; thealkyl, amino group having 1 to 4 carbon atoms may include methylamino,ethylamino, propylamino, butylamino groups and the like; anddialkylamino group having total carbon number of 2 to 8 may includedimethylamino, diethylamino, dipropylamino, dibutylamino groups and thelike.

Specific examples of the compound (I) to be used in the presentinvention are shown below.

3-Methyl-1-phenyl-2-pyrazolin-5-one;

3-Methyl-1-(2-methylphenyl)-2-pyrazolin-5-one;

3-Methyl-1-(3-methylphenyl)-2-pyrazolin-5-one;

3-Methyl-1-(4-methylphenyl)-2-pyrazolin-5-one;

3-Methyl-1-(3,4-dimethylphenyl)-2-pyrazolin-5-one;

1-(4-Ethylphenyl)-3-methyl-2-pyrazolin 5-one;

3-Methyl-1-(4-propylphenyl)-2-pyrazolin-5-one;

1-(4-Butylphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Trifluoromethylphenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Trifluoromethylphenyl)-3-methyl-2-pyrazolin-5-one;

1-(2-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3,4-Dimethyoxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Ethoxyphenyl)-3-methyl-2-pyrazolin-5-one;

3-Methyl-1-(4-propoxyphenyl)-2-pyrzolin-5-one;

1-(4-Butoxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(2-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;

1-(3,4-Dichlorophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Bromophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Fluorophenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Chloro-4-methylphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Methylmercaptophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Methylmercaptophenyl)-3-methyl-2-pyrazolin-5-one;

4-(3-Methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid;

1-(4-Ethoxycarbonylphenyl)-3-methyl-2-pyrazolin-5-one;

3-Methyl-1-(4-nitrophenyl)-2-pyrazolin-5-one;

3-Ethyl-1-phenyl-2-pyrazolin-5-one;

1-Phenyl-3-propyl-2-pyrazolin-5-one;

1,3-Diphenyl-2-pyrazolin-5-one;

3-Phenyl-1-(p-tolyl)-2-pyrazolin-5-one;

1-(4-Methoxyphenyl)-3-phenyl-2-pyrazolin-5-one;

1-(4-Chlorophenyl)-3-phenyl-2-pyrazolin-5-one;

3,4-Dimethyl-1-phenyl-2-pyrazolin-5-one;

4-Isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;

4-(2-Hydroxyethyl)-3-methyl-1-phenyl-2-pyrazolin-5-one;

3-Methyl-4-phenoxy-1-phenyl-2-pyrazolin-5-one;

3-Methyl-4phenylmercapto-1-phenyl-2-pyrazolin-5-one;

3,3a,4,5,6,7-Hexahydro-2-phenyl-2H-indazol-3-one;

3-(Ethoxycarbonylmethyl)-1-phenyl-2-pyrazolin-5-one;

1-Phenyl-2-pyrazolin-5-one;

3-Methyl-2-pyrazolin-5-one;

1,3-Dimethyl-2-pyrazolin-5-one;

1-Ethyl-3-methyl-2-pyrazolin-5-one;

1-Butyl-3-methyl-2-pyrazolin-5-one;

1-(2-Hydroxyethyl)-3-methyl-2-pyrazolin-5-one;

1-Cyclohexyl-3-methyl-2-pyrazolin-5-one;

1-Benzyl-1-methyl-2-pyrazolin-5-one;

1-(α-naphthyl)-3-methyl-2-pyrazolin-5-one;

1-Methyl-3-phenyl-2-pyrazolin-5-one;

1-Methyl-3-(4-methylphenyl)-2-pyrazolin-5-one;

1-(4-Butylphenyl)-3-phenyl-2-pyrazolin-5-one;

3-(4-Methoxyphenyl)-1-methyl-2-pyrazolin-5-one;

3-(4-Butoxyphenyl)-1-methyl-2-pyrazolin-5-one;

3-(4-Chlorophenyl)-1-methyl-2-pyrazolin-5-one;

3-(4-Hydroxyphenyl)-1-methyl-2-pyrazolin-5-one;

1-(3,4-Dihydroxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(2-Hydroxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3-Hydroxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Hydroxyphenyl)-3-methyl-2-pyrazolin-5-one;

1-(3,4-Hydroxyphenyl)-3-phenyl-2-pyrazolin-5-one;

1-(4-Hydroxyphenyl)-3-phenyl-2-pyrazolin-5-one;

1-(4-Hydroxymethylphenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Aminophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Methylaminophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Ethylaminophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Butylaminophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Dimethylaminophenyl)-3-methyl-2-pyrazolin-5-one;

1-(Acetamidophenyl)-3-methyl-2-pyrazolin-5-one;

1-(4-Cyanophenyl)-3-methyl-2-pyrazolin-5-one;

Some of the compounds to be used in the present invention are knowncompounds which can be used as the intermediate starting materials fordyes, etc., but their uses for pharmaceuticals have not been known.

Particularly, 3-methyl-1-phenyl-2-pyrazolin-5-one of the Formula (I-A):##STR10## is a known compound which is used as starting materials fordyes and is a metabolite of antipyrine Drug Metabolism and Disposition,6, 228 (1978)!, but its use as a pharmaceutical has not been known.However, this compound has been already evidenced to be high in safety(mouse intraperitoneal administration LD₅₀ 2012 mg/kg; rat oraladministration LD₅₀ 3500 mg/kg) Registry of Toxic Effects of ChemicalSubstances, 1981-1982! and also free from carcinogenicity NationalCancer Institute Report, 1978, 89!.

Pharmaceutically acceptable salts of the compound (I) to be used in thepresent invention include salts with mineral acids such as hydrochlorideacid, sulfuric acid, hydrobromic acid, phosphoric acid, etc.; salts withorganic acids such as methanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, acetic acid, glycolic acid, glucuronic acid,maleic acid, fumaric acid, oxalic acid, ascorbic acid, citric acid,salicylic acid, nicotinic acid, tartaric acid, etc.; salts with alkalimetals such as sodium potassium, etc.; salts with alkaline earth metalssuch as magnesium, calcium, etc.; salts with amines such as ammonia,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)-piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine,L-glucamine, etc.

The compounds to be used in the present invention can be synthesizedaccording to any desired method suited for the purpose, and an exampleof the preferable methods is shown below. ##STR11## wherein R₁, R₂ andR₃ have the same meanings as defined above, and R'represents an alkylgroup having 1 to 5 carbon atoms.

More specifically, the compound (I) can be obtained by allowing a β-ketoacid derivative represented by the Formula (II) and a hydradinederivative represented by the Formula (III) to react in either thepresence or absence of a solvent such as alcohols (e.g. methanol,ethanol, etc.) or aromatics (e.g. benzene, toluene, etc.), optionally inthe presence of a catalyst such as a base (e.g. potassium carbonate,sodium methoxide, sodium ethoxide, sodium hydroxide, potassiumhydroxide, sodium acetate, etc.), a mineral acid (e.g. hydrochloricacid, sulfuric acid, hydrobromic acid, etc.) or an organic acid (e.g.acetic acid, para-toluenesulfonic acid, etc.), at a temperature of 10°to 200° C.

Particularly, the compound (Formula I-A) as described above can beprepared by allowing ethyl acetoacetate and phenylhydradine to react inthe presence or absence of a solvent, optionally in the presence of acatalyst such as a base or an acid Beilstein, 24, 20!.

Also, depending on the substituent on the aryl group of R₃, desiredcompounds can be synthesized as shown below. ##STR12## wherein R₁, R₂and R' have the same meanings as defined above, and R" represents ahydrogen atom, an alkyl group having 1 to 5 carbon atoms or analkoxycarbonyl group having total carbon number of 2 to 6.

The desired compound wherein said substituent is a hydroxyl group can beobtained by, for example, decomposing an appropriate alkoxy group withhydrobromic acid or a Lewis acid. The desired compound wherein saidsubstituent is a hydroxymethyl group can be obtained by, for example,reducing a carboxylic acid or its derivative with an appropriatereducing agent such as lithium aluminum hydride, sodium boron hydride ordiborane. The desired compound wherein said substituent is an aminogroup can be obtained by, for example, reducing a nitro group underappropriate conditions with, for example, hydrogen-Pd/C, hydrochloricacid-stannic chloride.

In applying clinically the compound (I) in the case of using it orally,it is preferable to administer the compound (I) at a dose of 1 to 100 mg1 to 3 times/day for an adult (human). In the case of intravenousinjection, it is preferable to administer the compound (I) at a dose of0.01 to 10 mg 2 to 5 times/day for an adult or to inject these dosescontinuously by way of instillation. On the other hand, in the case ofintrarectal administration, it is preferable to administer the compound(I) at a dose of 1 to 100 mg 1 to 3 times/day. It is more preferable toincrease or decrease adequately the above doses depending on the age,the condition and specifics of the patient and/or the specifics of thedisease and symptoms. Other mammals would be treated within the samedosage range modified for relative body weight.

Also, in the case of oral or intrarectal administration, the compoundmay be used as a delayed-release preparation.

In forming preparations, it is generally practiced to use a compositioncontaining the compound (I) or at least one pharmaceutically acceptablesalts thereof together with a carrier, excepient or other additives forpharmaceuticals conventionally used. Pharmaceutical carriers may beeither solid or liquid, and examples of solid carriers include lactose,kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin,acacia, stearic acid, magnesium stearate, lecithin, sodium chloride,etc.

Examples of liquid carriers include syrup, glycerine, peanuts oil,polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol,propyleneglycol, water, etc.

Various preparation forms can be employed and, when using a solidcarrier, they can be formed into tablets, powders, granules, hardgelatin capsules, suppositories or troches. The amount of the solidcarrier can be widely varied, but it is preferably about 1 mg to about 1g.

When employing a liquid carrier, it can be made into a syrup, emulsion,soft gelatin capsules, further sterilized injectable solutions oraqueous or non-aqueous suspensions filled in ampoules.

Also, the compound (I) can be also used as a cyclodextrin clathratecompound thereof or through procedure of incorporating it in a liposome.

The prophylactic and therapeutic agent for circulatory disorders of thepresent invention has excellent actions, can be also administered orallyand is useful as prophylactic or therapeutic agent for circulatorydisorders accompanied with various ischemic diseases or various diseasesbased thereon, that is, cerebrovascular disorders such as cerebralinfarction, cerebral apoplexy, etc., or lowering in cerebral functionscaused by such disorders, various cerebral diseases such as vasculardementia, cerebrovascular tissue lesion, accompanied with aging, etc.,various heart diseases based on myocardial ischemia such as myocardialinfarction, cardiac insufficiency angina pectoris, etc., and variousperipheral circulation disorders, etc.

Further, the prophylactic and therapeutic agent for circulatorydisorders of the present invention is widely applicable for therapy oftrauma at the head portion, intracerebral hemorrhage, subarachidonichemorrhage, cerebral arterio-sclerosis, cerebral infarction, cerebralembolism, etc.; therapy at the acute stage of ischemic cerebrovasculardisorders caused by said diseases such as cerebral edema, etc.; therebyand prevention of recurrence of various diseases recognized at thesubacute stage and chronic stage of cerebrovascular disorders afterelongation of life after elapse of said acute stage, such as lowering incerebral dysfunctions, typically vascular dementia, etc.; therapy ofvarious cerebral diseases complicated by the advance of cerebrovasculartissue lesion accompanied with aging; clearing of obnubilation whichappears at the acute stage and chronic stage of cardiovasculardisorders; as well as emergence from anesthesia, etc. Also, it has aspecific feature, as different from TRH, of normalizing selectively onlythe electroencephalogram under abnormal state substantially withoutexhibiting any action on the electroencephalogram under normal state.

The present invention is described in more detail by referring tosynthetic examples and examples, but these are not intended to limit thescope of the present invention.

Synthetic example 1

Into 50 ml of ethanol, 13.0 g of ethyl acetoacetate and 10.8 g ofphenylhydrazine were added, and the mixture was refluxed under stirringfor 3 hours. After left to cool, the precipitated crystals were filteredand recrystallized from ethanol to obtain 11.3 g of3-methyl-1-phenyl-2-pyrazolin-5-one (Compound No. 1) as colorlesscrystals.

Yield 65%, m.p. 127.5°-128.5° C.

Synthetic examples 2-43

In the same manner as Synthetic example 1, the Compounds No. 2-43 shownin Table 1 were synthesized.

Synthetic example 44

An amount of 1.80 g of 1-(2-methoxyphenyl)-3-methyl-2-pyrazolin-5-onewas added into a mixture of 18 ml of 47% hydrobromic acid and 18 ml ofacetic acid, and the mixture were refluxed under stirring for 6.5 hours.After evaporation of the solvent, an aqueous NaHCO₃ solution was addedto the residue to adjust to pH 4 and the mixture was extracted withethyl acetate. The organic layer was dried and concentrated, followed byrecrystallization of the residue from ethanol to give 1.19 g of1-(2-hydroxyphenyl)-3-methyl-2-pyrazolin-5-one (Compound No. 44) ascolorless crystals.

Yield 67%, m.p. 212.5°-214° C.

Synthetic examples 45-48

In the same manner as Synthetic example 44, Compounds No. 45-48 shown inTable 1 were synthesized.

Synthetic example 49

Into 250 ml of anhydrous chloroform were added 5.0 g of4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 25 ml oftriethylamine and, further under ice-cooling, 12.5 ml of ethylchlorocarbonate was added dropwise into the mixture. After evaporationof the solvent, the residue was dissolved in 200 ml of THF, theinsolubles were filtered off, and then a solution of 2.08 g of NaBH₄dissolved in 60 ml of water was added dropwise into the filtrate,followed by stirring at room temperature for 2 hours. After evaporationof the solvent, water was added to the residue, and the mixture wasadjusted with dil. hydrochloric acid to pH 4-5 and then extracted withchloroform. The organic layer was dried, concentrated and purified onsilica gel column chromatograph with the use of chloroform-ethanl(100:1) as eluant, followed by recrystallization from chloroformethylether to give 1.16 g of1-(4-hydroxymethylphenyl)-3-methyl-2-pyrazolin-5-one as colorlesscrystals.

Yield 35%, m.p. 139°-140° C.

Synthetic example 50

Into 310 ml of methanol, 500 mg of3-methyl-1-(4-nitrophenyl)-2-pyrazolin-5-one was dissolved, 50 mg of 5%Pd/C and 0.6 ml of conc. hydrochloric acid were added to the solution,and the mixture was stirred under hydrogen atmosphere to consume thecalculated amount of hydrogen. Then, the catalyst was filtered off andthe filtrate was concentrated. The residue was recrystallized frommethanol-ethyl ether to give 409 mg of1-(4-aminophenyl)-3-methyl-2-pyrazolin-5-one dihydrochloride (CompoundNo. 50) as pale brown crystals.

Yield 68%, m.p. 196°-200° C.

Synthetic example 51

In the same manner as Synthetic example 1, the Compound No. 51 shown inTable 1 was synthesized.

EXAMPLE 1

(1) Inhibitory action of lipid peroxidation

(a) Preparation of brain homogenate

By use of Wister-strain male rat, brain homogenate was preparedfollowing the procedure as described below. Chest was opened underanesthesia by intraperitoneal administration of 45 mg/kg ofpentobarbital sodium, and a polyethylene tube was intubated into aortafrom left ventricle to be fixed therein. Next, a brain perfusion wasconducted through the tube with ice-cooled 50 mM phosphate-bufferedphysiological saline (pH 7.4) hereinafter referred to as "PBS"), and thewhole brain was extirpated. After removal of cerebellum, the wet weightof cerebrum was measured and, with addition of 9-fold amount of PBS, itwas broken by a Teflon homogenizer in ice-water to be homogenized. Afterthe brain homogenate was subjected to centrifugation at 4° C. at 2200rpm for 10 minutes, 0.3 ml of the supernatant was apportioned into alight-shielding test tube equipped with a ground stopper, to provide abrain homogenate for evaluation of medicine.

(b) Evaluation of test medicine

To the brain homogenate produced in (a), 0.6 ml of PBS and 10 μl ofethanolic solution of a test medicine were added (to a finalconcentration of 500 μM or a concentration at a common ratio of 3between 0.3 and 100 μm), and the mixture was heated in a warm bath at37° C. for 30 minutes. Subsequently, after addition of 200 μl of anaqueous 35% perchloric acid solution, centrifugation was effected at 4°C. at 2600 rpm for 10 minutes to obtain a supernatant. Also, the sameoperation was performed by addition of 10 μl of ethanol (blank) in placeof 10 μl ethanolic solution of the test medicine for measurement ofblank.

(c) Quantitative determination of peroxidized lipid

To 0.1 ml of the supernatant obtained in (b), 0.2 ml of aqueous 8.1%sodium dodecyl sulfate solution, 1.5 ml of 20% acetate buffer (pH 3.5),1.5 ml of aqueous 0.67% 2-thiobarbituric acid solution and 0.7 ml ofdistilled water, followed by mixing. Next, this mixture was heated in aboiling water bath for 60 minutes and then quenched with ice-water, and1.0 ml of distilled water and 5.0 ml of a pyridine-butanol mixture(1:15) were added. After shaking for about 30 seconds, the mixture wassubjected to centrifugation at 3000 rpm for 10 minutes, and thesupernatant was provided as a sample for measurement of peroxidizedlipid. A standard solution was prepared by addiing 0.1 ml ofLipoperoxide-test (containing 5 nmol/ml 1,1,3,3-tetraethoxypropane,produced by Wako Junyaku K.K.) in place of the brain homogenate obtainedin (b).

The peroxidized lipid was measured by use of a fluoroescentspectrophotometer (model 204, produced by Hitachi Seisakusho K.K.) at anexcitation wavelength of 515 nm and a fluorescence wavelength of 550 nm,and the peroxidized lipid quantity (TBA value) was determined accordingto the following formula: ##EQU1## Then, inhibitory ratios at respectiveconcentrations of test medicines relative to the TBA value of the blankin (b) were determined and IC₅₀ values were calculated according to theleast-squares method. The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                                                     IC.sub.50                    Compound                                         value                        No.   R.sub.1 R.sub.2  R.sub.3        m.p. (°C.)                                                                        (μM)                      __________________________________________________________________________     1    CH.sub.3                                                                              H                                                                                       ##STR13##     127.5˜128.5                                                                        18.2                          2    "       "                                                                                       ##STR14##     186˜188                                                                            392.2                         3    "       "                                                                                       ##STR15##     110.5˜112                                                                          8.0                           4    "       "                                                                                       ##STR16##       134˜134.5                                                                        6.3                           5    "       "                                                                                       ##STR17##     116˜119                                                                            6.0                           6    "       "                                                                                       ##STR18##       147-149.5                                                                              4.2                           7    "       "                                                                                       ##STR19##       96˜97.5                                                                          2.2                           8    "       "                                                                                       ##STR20##     124.5˜126                                                                          3.9                           9    "       "                                                                                       ##STR21##     156˜157                                                                            2129.0                       10    "       "                                                                                       ##STR22##     112.5˜113                                                                          7.1                          11    "       "                                                                                       ##STR23##     124˜125                                                                            20.7                         12    "       "                                                                                       ##STR24##     157˜158                                                                            23.0                         13    "       "                                                                                       ##STR25##     146.5˜148                                                                          10.3                         14    "       "                                                                                       ##STR26##       193˜194.5                                                                        97.8                         15    "       "                                                                                       ##STR27##       127˜127.5                                                                        3.4                          16    "       "                                                                                       ##STR28##     172˜173                                                                            4.0                          17    "       "                                                                                       ##STR29##     167.5˜169                                                                          1.6                          18    CH.sub.3                                                                              H                                                                                       ##STR30##     148˜149                                                                            12.1                         19    "       "                                                                                       ##STR31##     149˜150                                                                            4.1                          20    "       "                                                                                       ##STR32##     160˜162                                                                            5.1                          21    "       "                                                                                       ##STR33##     285 (decomposition)                                                                      (34.0%)*                     22    "       "                                                                                       ##STR34##       127˜127.5                                                                        5.2                          23    "       "                                                                                       ##STR35##     174˜176                                                                            5.1                          24    CH.sub.3 CH.sub.2                                                                     "                                                                                       ##STR36##      99.5-101.5                                                                              15.1                         25    CH.sub.3 CH.sub.2 CH.sub.2                                                            "        "              105˜106                                                                            5.9                          26                                                                                   ##STR37##                                                                            "        "              136.5˜138                                                                          0.08                         27    "       "                                                                                       ##STR38##     142˜144                                                                            1.2                          28    "       "                                                                                       ##STR39##     128˜130                                                                            3.0                          29    "       "                                                                                       ##STR40##     162.5˜164                                                                          1.2                          30    CH.sub.3                                                                              CH.sub.3                                                                                ##STR41##       129˜129.5                                                                        20.6                         31    "       (CH.sub.3).sub.2 CHCH.sub.2                                                            "              115˜117                                                                            5.7                          32    "       HOCH.sub.2 CH.sub.2                                                                    "              148˜149                                                                            (62.7%)*                     33    "                                                                                      ##STR42##                                                                             "              174˜178                                                                            16.2                         34    "                                                                                      ##STR43##                                                                             "                198˜199.5                                                                        146.4                        35    (CH.sub.2).sub.4                                                                                ##STR44##       174˜176.5                                                                        16.4                         36    EtOOCCH.sub.2                                                                         H        "              Oily product                                                                             32.2                         37    CH.sub.3                                                                              "        H                221˜222.5                                                                        (34.3%)*                     38    "       "        CH.sub.3       112˜113                                                                            (45.5%)*                     39    "       "        CH.sub.2 CH.sub.2 OH                                                                         104˜105                                                                            (39.2%)*                     40    "       "                                                                                       ##STR45##     148˜149                                                                            24.8                         41    "       "                                                                                       ##STR46##       172˜175.5                                                                        32.9                         42    "       "                                                                                       ##STR47##     165˜166                                                                            4.9                          43                                                                                   ##STR48##                                                                            "        CH.sub.3       210˜211                                                                            27.2                         44    CH.sub.3                                                                              "                                                                                       ##STR49##     212.5˜214                                                                          35.5                         45    "       "                                                                                       ##STR50##     196˜197                                                                            21.2                         46    "       "                                                                                       ##STR51##     230 (decomposition)                                                                      23.9                         47    "       "                                                                                       ##STR52##     196˜200 (decomposition)                                                            1.3                          48                                                                                   ##STR53##                                                                            "                                                                                       ##STR54##     202 (decomposition)                                                                      2.7                          49    CH.sub.3                                                                              H                                                                                       ##STR55##     139˜140                                                                            51.8                         50    "       "                                                                                       ##STR56##     196˜200                                                                            32.1                         51    H       "                                                                                       ##STR57##     117˜118                                                                            20.1                         __________________________________________________________________________     *Inhibitory percentage at 500 μM                                      

(2) Antagonistic action against drowsy pattern of soelectroencephalogram induced by phenobarbital or pentobarbital sodiumsalt

A Wistar-strain male rat weighing about 400 g was intramascularyadministered with 0.6 mg of d-tubocurarine to be immobilized and, whilemaintaining the rectal temperature at 37° to 38° C. under artificialrespiration, the electroencephalogram of the left cerebral frontalcortex was measured and recorded. Also, within the left femoral arteryand vein, cannulas for measurement of artery pressure and foradministration of medicine were placed, respectively.

As the active ingredient of the present invention, sodium salt of thecompound represented by Formula (I) was used and the respective doses ofsaid active ingredient and 30 mg/kg of phenobarbital sodium salt(produced by Iwaki Seiyaku K.K.) (hereinafter called "PHB") or 5 mg/kgof pentobarbital sodium salt (hereinafter called PBT) were eachdissolved in physiological saline and administered intravenously in aliquid amount of 1 ml/kg.

The action of the active ingredient of the present invention affectingthe cortex electroencephalogram after PHB or PBT administration wasinvestigated as follows; Namely, at the time of 5 minutes or later afterPHB or PBT administration when increase of the slow-wave component canbe clearly recognized on electroencephalogram, 1, 3, 10, 30 and 100mg/kg of the active ingredient were administered. To the control group 1ml/kg of physiological saline was intravenously administered.

Recording and analysis of electroencephalogram were continuously drawntogether with artery pressure, heart rate and rectal temperature on therecorder through a multi-purpose monitoring recording device (modelRM-85, produced by Nippon Koden K.K.). At the same time,electroencephalogram was recorded in data recorder (model A-65, producedby Sony K.K.), and compressed spectral array analysis was conducted bymeans of a computer for medical data processing (ATAC-450, produced byNippon Koden K.K.).

By administration of 30 mg/kg of PHB, the cerebral corticalelectroencephalogram becomes high voltage slow-wave, thus exhibitingclearly sleep-like electroencephalogram. Such an action persists for atleast 3 hours or longer after the administration.

In contrast, when the active ingredient of the present invention wasadministered even in an amount of 100 mg/kg, not only the drowsy patternof electroencephalogram as observed in the case of PHB, but also noappearance of low voltage fast-wave component (arousal pattern) wasrecognized at all.

From this fact, it has been found that the active ingredient of thepresent invention has no effect on normal electroencephalogram at alleven when administered in a large amount.

However, when the active ingredient of the present invention wasadministered during appearance of the drowsy pattern ofelectroencephalogram after PHB or PBT administration, the drowsy patternof electroencephalogram aws normalized depending on the dose thereof.The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Administered group Results                                                    ______________________________________                                        Compound 1         Antagonistic action                                                           at 1 mg/kg or higher                                       Compound 4         Antagonistic action                                                           at 10 mg/kg or higher                                      Compound 11        Antagonistic action                                                           at 10 mg/kg or higher                                      Compound 25        Antagonistic action                                                           at 10 mg/kg or higher                                      Compound 31        Antagonistic action                                                           at 10 mg/kg or higher                                      Control group      No antagonistic                                                               action                                                     ______________________________________                                    

(3) Protective action in cerebral ischemia recirculation model

A Wistar-strain male rat weighing about 400 g was administeredintramascularly with 0.6 mg of di-tubocurarine to be immobilized and,after a trachea cannulation, the head portion was fixed under artificialrespiration on a stereotaxic device. The head skin was cut open, cranialbone was bored, and then bipolar electrode for lead-out ofelectroencephalogram were placed on the surface of the subdural leftfrontal cerebral cortex. After the electrode was fixed with the cranialbone by use of dental cement, the animal was held on its back. Next, acannula for measurement of systemic pressure was placed within the leftfemoral artery, and a cannula for additional administration ofd-tubocurarine within the left femoral vein, respectively. The heartrate was measured and recorded by driving a heart rate meter with theartery wave.

After blood pressure, heart rate and various parameters ofelectroencephalogram were stabilized, 10 mg/kg of the active ingredientof the present invention prepared in a suspension so as to give 1 ml/kgin 1% tragacanth gum solution was administered directly into duodenum 30minutes after cerebral ischemia loading. To the control group, only the1% tragacanth gum solution of the same volume was administeredsimilarly.

Ten to twenty minutes after administration of the medicine, whilemonitoring the electroencephalogram, blood pressure and heart rate on amulti-purpose monitoring recording device (RM-85 model, produced byNippon Koden K.K.), the following operations were performed according tothe methods shown below for cerebral ischemia loading.

First, ribs were set free at the left costicartilage end to open thechest. Next, cerebral blood flow was blocked for ten minutes byobstructing the left common carotid artery and the left subclavianartery exposed at the aorta originating portion at the same time, andthen the brachiocephalic trunk by use of artery clips 30 minutes afteradministration of the medicine.

Recirculation of cerebral blood flow was effected by releasing at thesame time the two artery clips mounted on the respective sites asmentioned above.

The protective action of the medicine for the disorder afterrecirculation of cerebral ischemia was examined by the presence ofrestoration of electroencephalogram, and survival time of animal afterthe recirculation.

During the experiment, the rectal temperature of the animal wasmaintained at 37° to 38° C. by use of a warming mat. Also, the rectaltemperature was continuously drawn on the recorder together withelectroencephalogram, femoral artery pressure and heart rate.

When cerebral ischemia was loaded for 10 minutes, the voltage ofelectroencephalogram was lowered immediately after ischemia untilelectroencephalogram became disappeared and leveled after elapse ofabout 15 seconds. Such flattening of electroencephalogram during loadingof ischemia was recognized commonly in both of the control group and thegroup administered with the active ingredient of the present invention.

Even when cerebral ischemia for ten minutes was released andrecirculated, no appearance of electroencephalogram was recognized atall in all the cases of the control group . .flattering.!..Iadd.flattening .Iaddend.of electroencephalogram was continued to bemaintained similarly as during loading of ischemia. By persistence ofsuch a flattened electroencephalogram, the animals were dead 75 minutesafter recirculation on an average.

However, in the group administered with the active ingredient of thepresent invention, electroencephalogram appeared by restoration duringrecirculation period, whereby the function of the cardiovascular systemwere activated and normalized simultaneously with restoration of the socalled cerebral functions. As the overall results of these, the survivaltime of animals after recirculation was clearly elongated. The resultsare shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                     Presence of electroen-                                           Compound No. cephalogram restoration                                          ______________________________________                                        1            +                                                                4            +                                                                11           +                                                                13           +                                                                16           +                                                                25           +                                                                30           +                                                                31           +                                                                35           +                                                                40           +                                                                ______________________________________                                    

Further, particularly for the case of employing the compound representedby the formula (I-A) (Compound No. 1) as the active ingredient, its dosewas varied for evaluation of its protective action after recirculationof cerebral ischemia. As the result, in the group administered with theactive ingredient of the present invention electroencephalogram appearedby restoration during recirculation period depending on the dose of 3 to10 mg/kg, whereby the functions of the cardiovascular system wereactivated and normalized simultaneously with restoration of the socalled cerebral functions. As the overall result of these, the survivaltime of animals after the recirculation was clearly elongated. Theresults are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                             Survival Presence of                                                          time after                                                                             electro-                                                             recircu- encephalo-                                                                            Judge-                                  Administered                                                                              Animal   lation   gram    ment of                                 group       No.      (min.)   restoration                                                                           action*                                 ______________________________________                                        Active  3 mg/kg 1        85     +       +                                     ingredi-        2        126    -       -                                     ent of          average  106                                                  the    10 mg/kg 1        46     +       +                                     invention       2        140    +       +                                                     3        164    +       +                                                     average  117                                                  Control         1        54     -       -                                     group           2        70     -       -                                                     3        74     -       -                                                     4        76     -       -                                                     5        100    -       -                                                     average  75                                                   ______________________________________                                         *The case when restoration of electroencephalogram is judged as +, and th     case when not recognized as -.                                           

EXAMPLE 2 Protective action for myocardial ischemia

When coronary blood flow transporting nutritions to cardiac muscles isinterrupted (disorder in blood flow) or recirculated (disorder inrecirculation) by a certain cause, cardiac muscles will be damaged(disorder of mycardial ischemia). The degree of such disorder in cardiacmuscles will be advanced as the period of ischemia state is prolonged tocause various ischemic cardiac disorders such as the so-calledmyocardial infarction and cardiac insufficiency.

Accordingly, the protective effect of the Compound No. 1, as a typicalcompound, on cardiac muscles were examined as described below.

In the experiment, Wistar strain male rats weighing 300 to 400 g wereused. The heart was extirpated into a Krebs-Henseleit bicarbonate (KH)solution which had been oxygenated with 95% O₂ -5% CO₂, under anesthesiaby intraperitoneal administration of 50 mg/kg of pentobarbital sodium.Immediately after the isolation, a cannula was intubated into the aortaascendens, and perfusion was started according to the Langendorff method(75 cm H₂ O). Subsequently, the cannula was intubated into the leftartium. Then, perfusion in accordance with the Langerdorff method wasfurther conducted for 10 minutes, and then the left artium cannula wasopened change the mode of perfusion to that of the working heart method(preload 10 cm H₂ O, afterload 80 cm H₂ O) (American Journal ofPhysiology, 212, 804, 1967), which was conducted for 15 minutes. Next,in accordance with the method of Ichihara et al (Journal ofCardiovascular Pharmacology, 5, 745, 1983), the afterload on the aortawas released to provide an ischemic state in the cardiac muscles for 20minutes. Since five minutes before the initiation of the ischemic state,the perfusate was changed to the one containing the test medicine andsuch perfusate was used also during the period of the ischemic state.Reperfusion was conducted for 30 minutes with a perfusate containing notest medicine with the afterload of 80 cm H₂ O. In order to determinethe cardiac functions, coronal perfusion flow (CF), cardiac output (CO),heart rate (HR), aorta pressure (AP) and rate pressure product (HR×AP)were measured. The CF was measured by use of a 10 ml measuring cylinder.The CO was measured through a direct blood flow measuring probe (ModelFF-030, 30, produced by Nihon Kohden K.K.) disposed immediately in frontof the left artium cannula, by use of an electromagnetic blood flowmeter (Model MFV-2100, produced by Nihon Kohden K.K.) and an amplifierfor bioelectricity (Mode AB-621G, produced by Nihon Kohden K.K,). The APwas measured through a pressure transducer (Model MPU-0.5, produced byNihon Kohden K.K.) connected to the aortic cannula, by use of anamplifier for distortion pressure (Model AP-601G, produced by NihonKohden K.K.). The HR was measured by use of an cardiotacho meter (ModelAT-601G, produced by Nihon Kohden K.K.). The rate pressure product(HR×AP) was calculated by multiplying the HR by the aortic pressure.

As the perfusate, a KH solution, which had been oxygenated with 95% O₂-5% CO₂ and heated to 37° C. was used. The formulation of the KHsolution (unit: mM) is as follows. NaCl 118, KCl 4.7, CaCl₂ 2.5, MgSO₄1.2, KH₂ PO₄ 1.2, NaHCO₃ 25 and glucose 11.

Compound No. 1, the test medicine, was dissolved in one equivalent of anaqueous 1N-NaOH solution, followed by dilution in the KH solution foruse.

Changes in the cardiac functions after treatment with the test medicineand recovery thereof at reperfusion are indicated in terms of percentagebased on the value measured before the treatment with the test medicine.The results of the experiments are all shown in terms of the mean ±standard error.

When Compound No. 1 was used in order to find out the degree of therecovery of cardiac functions 30 minutes after reperfusion of the KHsolution after the cardiac ischemia loading was effected for 20 minutes,said Compound (1) showed an average recovery action of 24% based on thecardiac output (CO) as an index. However, in the negative control groupto which the same flow rate of physiological saline solution wasadministered in place of the Compound No. 1, said degree was found to be3% on an average, which is a negligible action (see Table 5).

                  TABLE 5                                                         ______________________________________                                        The cardiac output (CO) 30 minutes after the                                  reperfusion after myocardial ischemia loading was effected                                     Recovery of the cardiac                                                   N   output (CO) (%)                                              ______________________________________                                        Physiological  9     2.7 ± 1.8                                             saline solution                                                               Compound No. 1 5     23.8 ± 14.6                                           10.sup.-5 M                                                                   ______________________________________                                    

In Table 6, there is shown an example wherein the cardiac output (CO)reached 50% or more, 30 minutes after the reperfusion after ischemicloading was effected as an example of the recovery of the cardiacfunctions.

                  TABLE 6                                                         ______________________________________                                                     Number of recovery of                                                         the cardiac functions (%)                                        ______________________________________                                        Physiological saline                                                                         0/9 (0)                                                        solution                                                                      Compound No. 1 2/5 (40)                                                       ______________________________________                                    

The above results demonstrate that Compound (1) exhibits protectiveaction for myocardial ischemia.

The following components were mixed in a conventional manner and filledin soft capsules.

    ______________________________________                                        Active ingredient of the invention                                                                    10     mg                                             Olive oil               105    mg                                             Lecithin                6.5    mg                                             ______________________________________                                    

(3) Preparation for injection

The following components were mixed in a conventional manner and 1 mgampoules were prepared.

    ______________________________________                                        Active ingredient of the invention                                                                     0.7 mg                                               Sodium chloride          3.5 mg                                               Distilled water for injection                                                                          1.0 ml                                               ______________________________________                                    

We claim: . .1. A prophylactic and therapeutic pharmaceuticalcomposition for inhibiting lipid peroxidation by active oxygen, whichresults from ischemia, comprising: carrier..!.2. A method for inhibitingthe formation of peroxidized lipids in a mammal, as a result ofischemia, comprising administering an effective amount of a pyrazolonederivative of the formula: ##STR59## wherein R₁ represents a hydrogenatom, an aryl group, an alkyl group having 1 to 5 carbon atoms; R₂represents a hydrogen atom, an aryloxy group, an alkyl group having 1 to5 carbon atoms; or R₁ and R₂ taken together represent an alkylene grouphaving 3 to 5 carbon atoms; R₃ represents a cycloalkyl group having 5 to7 carbon atoms, a naphthyl group, or a phenyl group which isunsubstituted or para or meta substituted with 1 to 3 substituents whichare the same or different selected from the group consisting of alkylgroups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbonatoms, alkoxycarbonyl groups having a total carbon number of 2 to 5,alkylmercapto groups having 1 to 3 carbon atoms, halogen atoms, atrifluoromethyl group, a carboxyl group, a cyano group, a hydroxylgroup, a nitro group or a pharmaceutically acceptable salt thereof as anactive ingredient in a pharmaceutical carrier. . .3. A prophylactic andtherapeutic pharmaceutical composition for inhibiting the formation ofperoxidized lipids in a mammal and simultaneously providing antagonisticaction against drowsy pattern in an electroencephalogram caused bybarbituates, comprising an effective amount of a pyrazolone derivativeof the formula: ##STR60## wherein R₁ represents a hydrogen atom, an arylgroup, an alkyl group having 1 to 5 carbon atoms; R₂ represents ahydrogen atom, an aryloxy group, an alkyl group having 1 to 5 carbonatoms; or R₁ and R₂ taken together represent an alkylene group having 3to 5 carbon atoms; R₃ represents a cycloalkyl group having 5 to 7 carbonatoms, a naphthyl group, or a phenyl group which is unsubstituted orpara or meta substituted with 1 to 3 substituents which are the same ordifferent selected from the group consisting of alkyl groups having 1 to5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms, alkoxycarbonylgroups having a total carbon number of 2 to 5, alkylmercapto groupshaving 1 to 3 carbon atoms, halogen atoms, a trifluoromethyl group, acarboxyl group, a cyano group, a hydroxyl group, a nitro group or apharmaceutically acceptable salt thereof as an active ingredient in apharmaceutical carrier..!.4. A method for inhibiting the formation ofperoxidized lipids in a mammal and simultaneously to provideantagonistic action against drowsy pattern in an electroencephalogramcaused by barbituates, comprising administering an effective amount of apyrazolone derivative of the formula: ##STR61## wherein R₁ represents ahydrogen atom, an aryl group, an alkyl group having 1 to 5 carbon atoms;R₂ represents a hydrogen atom, an aryloxy group, an alkyl group having 1to 5 carbon atoms; or R₁ and R₅ taken together represent an alkylenegroup having 3 to 5 carbon atoms; R₃ represents a cycloalkyl grouphaving 5 to 7 carbon atoms, a naphthyl group, or a phenyl group which isunsubstituted or para or meta substituted with 1 to 3 substituents whichare the same or different selected from the group consisting of alkylgroups having 1 to 5 carbon atoms, alkoxy groups having 1 to 5 carbonatoms, alkoxycarbonyl groups having a total carbon number of 2 to 5,alkylmercapto groups having 1 to 3 carbon atoms, halogen atoms, atrifluoromethyl group, a carboxyl group, a cyano group, a hydroxylgroup, a nitro group or a pharmaceutically acceptable salt thereof as anactive ingredient in a pharmaceutical carrier. . .5. The compositionaccording to claim 1 or 3, wherein the aryl group represented by R₁ is aphenyl group or phenyl groups which are substituted with a methyl group,a butyl group, a methoxy group, a butoxy group, a hydroxyl group or achlorine atom; the alkyl group having 1 to 5 carbon atoms represented byR₁, R₂ or R₃ is a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, an isobutyl group, a sec-butyl group, atert-butyl group or a pentyl group; the alkoxycarbonylalkly group havingtotal carbon number of 3 to 6 represented by R₁ is amethoxycabonylmethyl group, an ethoxycarbonylmethyl group, apropoxycarbonylmethyl group, a methoxycarbonylethyl group or amethoxycarbonylpropyl group; the aryloxy group represented by R₂ is aphenoxy group, a p-methylphenoxy group, a p-methoxyphenoxy gorup, ap-chlorophenoxy group or a p-hydroxyphenoxy group; the arylmercaptogroup represented by R₂ is a phenylmercapto group, ap-methylphenylmercapto group, a p-methoxyphenylmercapto group, ap-chlorophenylmercapto group or a p-hydroxphenylmercapto group; thehydroxyalkyl group having 1 to 3 carbon atoms represented by R₂ R₃ is ahydroxymethyl group, a 2-hydroxyethyl group or a 3-hydroxpropyl group;the cycloalkyl group having 5 to 7 carbon atoms represented by R₃ is acyclopentyl group, a cyclohexyl group or a cycloheptyl group; as thesubstituent for the phenyl group in the definition of R₃, the alkoxygroup having 1 to 5 carbon atoms is a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group, a butoxy group or a pentyloxy group;the alkoxycarbonyl group having a total carbon number of 2 to 5 is amethoxycarbonyl group, an ethyoxycarbonyl group, a propoxycarbonyl groupor a butoxycarbonyl group; the alkylmercapto group having 1 to 3 carbonatoms is a methylmercapto group, an ethylmercapto group or apropylmercapto group; the alkylamino group having 1 to 4 carbon atoms isa methylamino group, an ethylmino group, a propylamino group or abutylamino group and the dialkylamino group having a total carbon numberof 2 to 8 is a diemthylamino group, a diethylamino group, adipropylamino group or a dibutylamino group..!.. .6. The compositionaccording to claim 1 or 3, wherein said pyrazolone derivative isselected from the group consistingof,3-Methyl-1-phenyl-2-pyrazolin-5-one;3-Methyl-1-(4-methylphenyl)-2-pyrazolin-5-one;1-(4-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Ethoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;1-Phenyl-3-propyl-3-pyrazolin-5-one;3,4-Dimethyl-1-phenyl-2-pyazolin-5-one,4-Isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;3,3a,4,5,6,7-Hexahydro-2-phenyl-2H-indazol-3-one; and1-Cyclohexyl-3-methyl-2-pyazolin-5-oneor a pharmaceutically acceptablesalt thereof..!.. .7. The composition according to claim 1 or 3, whereinsaid circulatory disorders are ischematic diseases..!.. .8. Thecomposition according to claim 1 or 3, wherein said agent is useful asan inhibitor against lipid peroxidtion..!.. .9. The compositionaccording to claim 1 or 3, wherein 3-methyl-1-phenyl-2-pyrazolin-5-oneor a pharmaceutically acceptable salt thereof as an active ingredient isuseful as an agent for normalizing cerebral functions..!.10. The methodof claim 2 or 4, wherein said pyrazolone derivative is3-methyl-1-phenyl-2-pyrazolin-5-one.
 11. The method of claim 2 or 4,wherein said pyrazolone derivative is3-methyl-1-(4-methylphenyl)-2-pyrazolin-5-one.
 12. The method of claim 2or 4, wherein said pyrazolone derivative is1-(4-methoxyphenyl)-3-methyl-2-pyrazolin-5-one.
 13. The method of claim2 or 4, wherein said pyrazolone derivative is(4-ethoxyphenyl)-3-methyl-2-pyrazolin-5-one.
 14. The method of claim 2or 4, wherein said pyrazolone derivative is1-(4-chlorophenyl)-3-methyl-2-pyrazolin-5-one.
 15. The method of claim 2or 4, wherein said pyrazolone derivative is1-phenyl-3-propyl-2-pyazolin-5-one.
 16. The method of claim 2 or 4,wherein said pyrazolone derivative is3,4-dimethyl-1-phenyl-2-pyazolone-5-one.
 17. The method of claim 2 or 4,wherein said pyrazolone derivative is4-isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one.
 18. The method of claim2 or 4, wherein said pyrazolone derivative is3,3a,4,5,6,7-hexahydro-2-phenyl-2H-indazol-3-one.
 19. The method ofclaim 2 or 4, wherein said pyrazolone derivative is1-cyclohexyl-3-methyl-2-pyrazolin-5-one. .Iadd.20. A pharmaceuticalcomposition comprising 1-100 mg/kg of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor cerebral, cardiac or peripheral circulatory disorders in mammals..Iaddend..Iadd.21. A pharmaceutical composition according to claim 20wherein said disorder is myocardial infarction or cardiac insufficiency..Iaddend..Iadd.22. A pharmaceutical composition according to claim 20wherein said disorder is cerebral ischemia. .Iaddend..Iadd.23. Apharmaceutical composition according to claim 20 wherein said disorderis cerebral infarction, cerebral embolism or subarachidonic hemorrhage..Iaddend..Iadd.24. A pharmaceutical composition comprising 1-100 mg/kgof 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the treatment of trauma in mammals. .Iaddend..Iadd.25. Apharmaceutical composition comprising 1-100 mg/kg of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the prevention of the recurrence of cerebrovascular disorders inmammals. .Iaddend..Iadd.26. A pharmaceutical composition comprising1-100 mg/kg of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceuticallyacceptable salt thereof in a pharmaceutical carrier to provide atherapeutic action for mammals during the emergence from anesthesia..Iaddend..Iadd.27. A pharmaceutical composition comprising 1-100 mg/kgof a pyrazolone derivative to provide a prophylactic and therapeuticaction for cerebral, cardiac or peripheral circulatory disorders inmammals, said derivative having the formula: ##STR62## wherein R₁represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5carbon atoms; R₂ represents a hydrogen atom, an aryloxy group, an alkylgroup having 1 to 5 carbon atoms; or R₁ and R₂ taken together representan alkylene group having 3 to 5 carbon atoms; R₃ represents a cycloalkylgroup having 5 to 7 carbon atoms, a naphthyl group, or a phenyl groupwhich is unsubstituted or para or meta substituted with 1 to 3substituents which are the same or different selected from the groupconsisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groupshaving 1 to 5 carbon atoms, alkoxycarbonyl groups having a total carbonnumber of 2 to 5, alkylmercapto groups having 1 to 3 carbon atoms,halogen atoms, a trifluoromethyl group, a carboxyl group, a cyano group,a hydroxyl group, and a nitro group; or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier. .Iaddend..Iadd.28. Apharmaceutical composition in accordance with claim 27, said compositioncomprising an effective amount of the pyrazolone to provide aprophylactic and therapeutic action for cerebral, cardiac or peripheralcirculatory disorders accompanied by an ischemic disease..Iaddend..Iadd.29. A pharmaceutical composition in accordance with claim28, said composition comprising an effective amount of the pyrazolone toprovide a prophylactic and therapeutic action for a peripheralcirculatory disorder accompanied by an ischemic disease..Iaddend..Iadd.30. A pharmaceutical composition in accordance with claim27, said composition comprising an effective amount of the pyrazolone toprovide a prophylactic and therapeutic action for myocardial ischemia orangina pectoris accompanied by an ischemic disease. .Iaddend..Iadd.31. Apharmaceutical composition in accordance with claim 27, said compositioncomprising an effective amount of the pyrazolone to provide aprophylactic and therapeutic action for a disorder a cerebrovasculardisorder or a lowering in cerebral functions accompanied by an ischemicdisease. .Iaddend..Iadd.32. A pharmaceutical composition in accordancewith claim 27, said composition comprising an effective amount of thepyrazolone to provide a prophylactic and therapeutic action for adisorder selected from the group consisting of cerebral apoplexy,cerebral infarction, ischemic cerebrovascular disorders, subarachnoidichemorrhage, intracerebral hemorrhage, cerebral embolism, cerebral edema,trauma, vascular dementia, cerebrovascular tissue lesion, cerebralarteriosclerosis and obnubilation. .Iaddend..Iadd.33. A pharmaceuticalcomposition in accordance with claim 27 wherein the aryl grouprepresented by R₁ is a phenyl group or phenyl groups which aresubstituted with a methyl group, a butyl group, a methoxy group, abutoxy group, a hydroxyl group or a chlorine atom; the alkyl grouphaving 1 to 5 carbon atoms represented by R₁ or R₂ is a methyl group, anethyl group, a propyl group, an isopropyl group, a butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group or a pentyl group;the aryloxy group represented by R₂ is a phenoxy group, ap-methylphenoxy group, a p-methoxphenoxy group, a p-chlorophenoxy groupor a p-hydroxyphenoxy group; the cycloalkyl group having 5 to 7 carbonatoms represented by R₃ is a cyclopentyl group, a cyclohexyl group or acycloheptyl group; as the substituent for the phenyl group in thedefinition of R₃, the alkoxy group having 1 to 5 carbon atoms is amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group or a pentyloxy group; the alkoxycarbonyl group having atotal carbon number of 2 to 5 is a methoxycarbonyl group, anethyoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonylgroup; the alkylmercapto group having 1 to 3 carbon atoms is amethylmercapto group, an ethylmercapto group or a propylmercapto group..Iaddend..Iadd.34. A pharmaceutical composition in accordance with claim27 wherein said pyrazolone derivative is selected from the groupconsisting of:3-Methyl-1-phenyl-2-pyrazolin-5-one;3-Methyl-1-(4-methylphenyl)-2-pyrazolin-5-one;1-(4-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Ethoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;1-Phenyl-3-propyl-3-pyrazolin-5-one;3,4-Dimethyl-1-phenyl-2-pyrazolin-5-one;4-Isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;3,3a,4,5,6,7-Hexahydro-2-phenyl-2H-indazol-3-one; and1-Cyclohexyl-3-methyl-2-pyrazolin-5-oneor a pharmaceutically acceptablesalt thereof. .Iaddend..Iadd.35. A pharmaceutical composition inaccordance with claim 27, said composition comprising an effectiveamount of the pyrazolone to act as an inhibitor against lipidperoxidation. .Iaddend..Iadd.36. A pharmaceutical composition inaccordance with claim 27 wherein 3 methyl-1-phenyl-2-pyrazolin-5-one ora pharmaceutically acceptable salt thereof is useful as an agent fornormalizing cerebral functions. .Iaddend..Iadd.37. A method forproviding a therapeutic action comprising administering an effectiveamount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceuticallyacceptable salt thereof in a pharmaceutical carrier to provide atherapeutic action for cerebral, cardiac or peripheral circulatorydisorders in mammals. .Iaddend..Iadd.38. A method according to claim 37wherein said disorder is myocardial infarction or cardiac insufficiency..Iaddend..Iadd.39. A method according to claim 37 wherein said disorderis cerebral ischemia. .Iaddend..Iadd.40. A method according to claim 37wherein said disorder is cerebral infarction, cerebral embolism orsubarachidonic hemorrhage. .Iaddend..Iadd.41. A method according toclaim 37 wherein said effective amount is from about 1 to about 100 mgof said compound and is orally administered 1 to 3 times/day..Iaddend..Iadd.42. A method according to claim 37 wherein said effectiveamount is from about 0.01 to about 10 mg of said compound and isintravenously administered 2 to 5 times/day. .Iaddend..Iadd.43. A methodaccording to claim 37 wherein said effective amount is administeredcontinuously by instillation. .Iaddend..Iadd.44. A method according toclaim 37 wherein said effective amount is from about 1 to about 100 mgof said compound and is intrarectally administered 1 to 3 times/day..Iaddend..Iadd.45. A method for providing a therapeutic actioncomprising administering an effective amount of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the treatment of trauma in mammals. .Iaddend..Iadd.46. A method forproviding a therapeutic action comprising administering an effectiveamount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceuticallyacceptable salt thereof in a pharmaceutical carrier to provide atherapeutic action for mammals during the emergence from anesthesia..Iaddend..Iadd.47. A method for providing a therapeutic actioncomprising administering an effective amount of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the prevention of recurrence of cerebrovascular disorders inmammals. .Iaddend..Iadd.48. A method for providing a prophylactic andtherapeutic action comprising administering an effective amount ofpyrazolone derivative to provide a prophylactic and therapeutic actionfor cerebral, cardiac or peripheral circulatory disorders in mammals,said derivative having the formula: ##STR63##.Iaddend.wherein R₁represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5carbon atoms; R₂ represents a hydrogen atom, an aryloxy group, an alkylgroup having 1 to 5 carbon atoms; or R₁ and R₂ taken together representan alkylene group having 3 to 5 carbon atoms; R₃ represents a cycloalkylgroup having 5 to 7 carbon atoms, a naphthyl group, or a phenyl groupwhich is unsubstituted or para or meta substituted with 1 to 3substituents which are the same or different selected from the groupconsisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groupshaving 1 to 5 carbon atoms, alkoxycarbonyl groups having a total carbonnumber of 2 to 5, alkylmercapto groups having 1 to 3 carbon atoms,halogen atoms, a trifluoromethyl group, a carboxyl group, a cyano group,a hydroxyl group, a nitro group or a pharmaceutically acceptable saltthereof in a pharmaceutical carrier. .Iadd.49. A method according toclaim 48 wherein said disorder is accompanied by an ischemic disease..Iaddend..Iadd.50. A method according to claim 49 wherein saidcirculatory disorder said disorder is a peripheral circulatory disorder..Iaddend..Iadd.51. A method according to claim 48 wherein said cardiacdisorder is myocardial ischemia or angina pectoris. .Iaddend..Iadd.52. Amethod according to claim 48 wherein said cerebral disorder is acerebrovascular disorder or a lowering in cerebral functions..Iaddend..Iadd.53. A method according to claim 48 wherein said cerebraldisorder is selected from the group consisting of cerebral apoplexy,cerebral infarction, ischemic cerebrovascular disorders, subarachnoidichemorrhage, intracerebral hemorrhage, cerebral embolism, cerebral edema,trauma, vascular dementia, cerebrovascular tissue lesion, cerebralarteriosclerosis and obnubilation. .Iaddend..Iadd.54. A method accordingto claim 48 wherein the aryl group represented by R₁ is a phenyl groupor phenyl groups which are substituted with a methyl group, a butylgroup, a methoxy group, a butoxy group, a hydroxyl group or a chlorineatom; the alkyl group having 1 to 5 carbon atoms represented by R₁ or R₂is a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group ora pentyl group; the aryloxy group represented by R₂ is a phenoxy group,a p-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxygroup or a p-hydroxyphenoxy group; the cycloalkyl group having 5 to 7carbon atoms represented by R₃ is a cyclopentyl group, a cyclohexylgroup or a cycloheptyl group; as the substituent for the phenyl group inthe definition of R₃, the alkoxy group having 1 to 5 carbon atoms is amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group or a pentyloxy group; the alkoxycarbonyl group having atotal carbon number of 2 to 5 is a methoxycarbonyl group, anethyoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonylgroup; the alkylmercapto group having 1 to 3 carbon atoms is amethylmercapto group, an ethylmercapto group or a propylmercapto group..Iaddend..Iadd.55. A method according to claim 48 wherein saidpyrazolone derivative is selected from the group consistingof:3-Methyl-1-phenyl-2-pyrazolin-5-one;3-Methyl-1-(4-methylphenyl)-2-pyrazolin-5-one;1-(4-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Ethoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;1-Phenyl-3-propyl-3-pyrazolin-5-one;3,4-Dimethyl-1-phenyl-2-pyrazolin-5-one;4-Isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;3,3a,4,5,6,7-Hexahydro-2-phenyl-2H-indazol-3-one; and1-Cyclohexyl-3-methyl-2-pyrazolin-5-one;or a pharmaceutically acceptablesalt thereof. .Iaddend..Iadd.56. A method according to claim 48 whereinsaid composition is useful as an inhibitor against lipid peroxidation..Iaddend..Iadd.57. A method according to claim 48 wherein 3methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptable saltthereof is useful as an agent for normalizing cerebral functions..Iaddend..Iadd.58. A pharmaceutical composition comprising 0.01-100 mgof 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor cerebral, cardiac or peripheral circulatory disorders in mammals..Iaddend..Iadd.59. A pharmaceutical composition according to claim 58,said composition comprising an effective amount of the pyrazolone toprovide a prophylactic and therapeutic action for myocardial infarctionor cardiac insufficiency. .Iaddend..Iadd.60. A pharmaceuticalcomposition according to claim 58, said composition comprising aneffective amount of the pyrazolone to provide a prophylactic andtherapeutic action for cerebral ischemia. .Iaddend..Iadd.61. Apharmaceutical composition according to claim 58, said compositioncomprising an effective amount of the pyrazolone to provide aprophylactic and therapeutic action for cerebral infarction, cerebralembolism or subarachnoidic hemorrhage. .Iaddend..Iadd.62. Apharmaceutical composition comprising 0.01-100 mg of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the treatment of trauma in mammals. .Iaddend..Iadd.63. Apharmaceutical composition comprising 0.01-100 mg of3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier to provide a therapeutic actionfor the prevention of the recurrence of cerebrovascular disorders inmammals. .Iaddend..Iadd.64. A pharmaceutical composition comprising0.01-100 mg of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceuticallyacceptable salt thereof in a pharmaceutical carrier to provide atherapeutic action for mammals during the emergence from anesthesia..Iaddend..Iadd.65. A pharmaceutical composition comprising 0.01-100 mgof a pyrazolone derivative to provide a prophylactic and therapeuticaction for cerebral, cardiac or peripheral circulatory disorders inmammals, said derivative having the formula: ##STR64## wherein R₁represents a hydrogen atom, an aryl group, an alkyl group having 1 to 5carbon atoms; R₂ represents a hydrogen atom, an aryloxy group, an alkylgroup having 1 to 5 carbon atoms; or R₁ and R₂ taken together representan alkylene group having 3 to 5 carbon atoms; R₃ represents a cycloalkylgroup having 5 to 7 carbon atoms, a naphthyl group, or a phenyl groupwhich is unsubstituted or para or meta substituted with 1 to 3substituents which are the same or different selected from the groupconsisting of alkyl groups having 1 to 5 carbon atoms, alkoxy groupshaving 1 to 5 carbon atoms, alkoxycarbonyl groups having a total carbonnumber of 2 to 5, alkylmercapto groups having 1 to 3 carbon atoms,halogen atoms, a trifluoromethyl group, a carboxyl group, a cyano group,a hydroxyl group, and a nitro group; or a pharmaceutically acceptablesalt thereof in a pharmaceutical carrier. .Iaddend..Iadd.66. Apharmaceutical composition in accordance with claim 65, said compositioncomprising an effective amount of the pyrazolone to provide aprophylactic and therapeutic action for cerebral, cardiac or peripheralcirculatory disorders accompanied by an ischemic disease..Iaddend..Iadd.67. A pharmaceutical composition in accordance with claim65, said composition comprising an effective amount of the pyrazolone toprovide a prophylactic and therapeutic action for a peripheralcirculatory disorder accompanied by an ischemic disease..Iaddend..Iadd.68. A pharmaceutical composition in accordance with claim65, said composition comprising an effective amount of the pyrazolone toprovide a prophylactic and therapeutic action for myocardial ischemia orangina pectoris accompanied by an ischemic disease. .Iaddend..Iadd.69. Apharmaceutical composition in accordance with claim 65, said compositioncomprising an effective amount of the pyrazolone to provide aprophylactic and therapeutic action for a cerebrovascular disorder or alowering in cerebral functions accompanied by an ischemic disease..Iaddend..Iadd.70. A pharmaceutical composition in accordance with claim58 or 65, said composition comprising an effective amount of thepyrazolone to provide a prophylactic and therapeutic action for adisorder selected from the group consisting of cerebral apoplexy,cerebral infarction, ischemic cerebrovascular disorders, subarachnoidichemorrhage, intracerebral hemorrhage, cerebral embolism, cerebral edema,trauma, vascular dementia, cerebrovascular tissue lesion, cerebralarteriosclerosis and obnubilation. .Iaddend..Iadd.71. A pharmaceuticalcomposition in accordance with claim 65 wherein the aryl grouprepresented by R₁ is a phenyl group or phenyl groups which aresubstituted with a methyl group, a butyl group, a methoxy group, abutoxy group, a hydroxyl group or a chlorine atom; the alkyl grouphaving 1 to 5 carbon atoms represented by R₁ or R₂ is a methyl group, anethyl group, a propyl group, an isopropyl group, a butyl group, anisobutyl group, a sec-butyl group, a tert-butyl group or a pentyl group;the aryloxy group represented by R₂ is a phenoxy group, ap-methylphenoxy group, a p-methoxyphenoxy group, a p-chlorophenoxy groupor a p-hydroxyphenoxy group; the cycloalkyl group having 5 to 7 carbonatoms represented by R₃ is a cyclopentyl group, a cyclohexyl group or acycloheptyl group; as the substituent for the phenyl group in thedefinition of R₃, the alkoxy group having 1 to 5 carbon atoms is amethyl group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group or a pentyloxy group; the alkoxycarbonyl gross having atotal carbon number of 2 to 5 is a methoxycarbonyl group, anethyoxycarbonyl group, a propoxycarbonyl group or a butoxycarbonylgroup; the alkylmercapto group having 1 to 3 carbon atoms is amethylmercapto group, an ethylmercapto group or a propylmercapto group..Iaddend..Iadd.72. A pharmaceutical composition in accordance with claim65 wherein said pyrazolone derivative is selected from the groupconsisting of:3-Methyl-1-phenyl-2-pyrazolin-5-one;3-Methyl-1-(4-methylphenyl)-2-pyrazolin-5-one;1-(4-Methoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Ethoxyphenyl)-3-methyl-2-pyrazolin-5-one;1-(4-Chlorophenyl)-3-methyl-2-pyrazolin-5-one;1-Phenyl-3-propyl-3-pyazolin-5-one;3,4-Dimethyl-1-phenyl-2-pyrazolin-5-one;4-Isobutyl-3-methyl-1-phenyl-2-pyrazolin-5-one;3,3a,4,5,6,7-Hexahydro-2-phenyl-2H-indazol-3-one; and1-Cyclohexyl-3-methyl-2-pyrazolin-5-one; or a pharmaceuticallyacceptable salt thereof. .Iaddend..Iadd.73. A pharmaceutical compositionin accordance with claim 65, said composition comprising an effectiveamount of the pyrazolone to act as an inhibitor against lipidperoxidation. .Iaddend..Iadd.74. A pharmaceutical composition inaccordance with claim 65, said composition comprising an effectiveamount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a pharmaceuticallyacceptable salt thereof to act as an agent for normalizing cerebralfunctions. .Iaddend.